Favezelimab (anti–LAG-3) plus pembrolizumab in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after anti–PD-1 treatment: An open-label phase 1/2 study.
Authors: John Timmerman, David Lavie, Nathalie A. Johnson, Abraham Avigdor, Peter Borchmann, Charalambos Andreadis, Ali Bazargan, Gareth Gregory, Colm Keane, Tzoran Inna, Vladan Vucinic, Pier Luigi Zinzani, Hong Zhang, Pallavi Pillai, Patricia Marinello, Alex Francisco Herrera
Journal: Journal of Clinical Oncology (2022)

7545 Background: PD-1 inhibitors are a standard of care for R/R cHL but optimal therapy after anti–PD-1 therapy failure is yet to be defined. LAG-3/PD-1 coblockade has demonstrated antitumor activity in preclinical models. This multicohort phase 1/2 study (NCT03598608) evaluated the safety and efficacy of favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, plus the PD-1 inhibitor pembrolizumab (pembro) in pts with R/R hematologic malignancies. Cohort 2 focused on pts with R/R cHL refractory to anti–PD-1 therapy. Methods: This study included a safety lead-in phase (part 1) to determine recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible pts in cohort 2 had R/R cHL, relapsed after or were ineligible for autologous stem cell transplantation (ASCT), and progressed after ≥2 doses of anti–PD-1 therapy (within 12 weeks of last dose). In part 1, pts from all cohorts received pembro IV 200 mg Q3W and favezelimab IV 200 mg or 800 mg Q3W. Dose-finding based on occurrence of dose-limiting toxicities (DLT) was determined using an mTPI design. In part 2, pts received pembro + favezelimab at the established RP2D for up to 35 cycles. Primary end point was safety. Secondary end point was ORR. DOR, PFS, and OS were exploratory. Results: Only 1 DLT (autoimmune hepatitis [grade 4]) was observed among the first 6 pts from all cohorts in part 1 at the favezelimab 200 mg dose; thus, the dose was escalated to 800 mg. No DLTs were observed in 15 additional pts at the 800 mg dose. Favezelimab RP2D was defined as 800 mg Q3W + pembro 200 mg Q3W. In cohort 2, 33 pts were enrolled; median age was 37 yrs, 64% had ECOG PS 0, and 94% had ≥4 prior lines of therapy. After a median follow-up of 16.5 mo, ORR for pts receiving favezelimab 800 mg (n = 29) was 31% (95% CI, 15-51; CR, 2 [7%]; PR, 7 [24%]); 66% of responders had an anti–PD-1–based regimen as most recent line of therapy at study entry. 23 of 29 pts (79%) had reduction from baseline in target lesions. Median DOR for pts who received favezelimab 800 mg was not reached (NR; 95% CI, 0+ to 14+ mo). For all pts in cohort 2, median PFS was 9 mo (95% CI, 5-15); 12-mo PFS rate was 39%. Median OS was 26 mo (95% CI, 26-NR); 12-mo OS rate was 91%. At database cutoff (Nov 1, 2021), 20 pts discontinued treatment (7 AEs, 11 PD/clinical progression, 2, withdrawal/physician decision). TRAEs occurred in 28 pts (85%); most common ( &gt; 10%) were hypothyroidism (18%), nausea and fatigue (15% each), and arthralgia and diarrhea (12% each); grade 3 or 4 TRAEs occurred in 6 pts (18%); 18% discontinued treatment due to TRAEs. No treatment-related deaths occurred. Conclusions: Favezelimab 800 mg + pembro 200 mg Q3W showed a tolerable safety profile and effective antitumor activity in heavily pretreated pts with R/R cHL whose disease had progressed after anti–PD-1 therapy, suggesting that the combination may reinduce a response in these pts. Clinical trial information: NCT03598608.